Study of inherited visual diseases provides a means by which both normal and aberrant visual processes might be understood. In addition to directly elucidating the pathophysiology of the inherited disease under study, these studies can provide insights into the structure-function relationships of t molecular components of the visual system and their normal physiology. This laboratory is using a number of approaches to study inherited visual diseases affecting the lens and retina. Lens crystallins make up more than 90 percent of the soluble protein of the lens and are heavily modified in most cataracts. The effects that specific modifications of beta- and gamma-crystallin structure produce on crystallin functions such as stability and formation of macromolecular aggregates are being expressed using SF9 cells transformed with bacculovirus vector containing coding sequences for normal and modified beta A3/A1- and beta A2-crystallin genes. Regions of the beta-crystallin molecule of special interest include the amino and carboxy terminal arms, the connecting peptide, and the Greek key motifs of the core domains. In addition, the interactions of acidic and basic beta-crystallins are being studied. A second approach to understanding inherited visual diseases uses principles of positional cloning to identify genes important in human inherited diseases. Human diseases currently undergoing linkage analysis, gene isolation, or characterization of mutations include Usher syndrome, lo QT syndrome, cataracts, and a variety of X-linked syndromes. We are currently collecting families with autosomal recessive retinitis pigmentosa and Bietti syndrome in preparation for study of this important group of diseases. Finally, the effects of specific genetic alterations, including d pigment gene polymorphisms and glutathione S-transferase M1 deletions on the visual process, are being studied.